The long range goal of the proposed research is to understand how cell polarity is controlled during metazoan development. Genes that control the cell polarity of individual cells in the nematode C. elegans will be identified and studied using genetic and molecular methods. Mutations in one such gene, lin-44, cause the polarity of certain cells in the tall to be reversed with respect to the body axis. Lin-44 encodes a WNT protein, is expressed by the skin cells at the tip of the animal's tail and functions to specify the polarity of more anterior tall cells. The Wnt gene family encode secretory glycoproteins that act as short-range signaling molecules involved in many developmental processes in many different species. The first member of the Wnt family was isolated as a proto-oncogene that when activated caused murine breast cancer. One goal of this work is to understand how a WNT signal from cells in the tip of the tail influences the polarities of the cells that receive the signal. Novel genes that interact with C. elegans WNT gene lin-44 to control cell polarity will be identified by identifying mutations that disrupt the polarities of cells whose polarities are controlled by lin-44. Preliminary genetic screens have already identified two such genes, lop-1 and lop- 2. Genetic screens will also be used to identify mutations that act to suppress the polarity defects caused by lin-44 mutations. These newly identified genes might be involved in the production and secretion of LIN-44 signal, the reception and transduction of the signal, or the execution of the polarity information carried by LIN 44. Genetic and phenotypic characterization of the two newly identified genes that function in the control of cell polarity, lop-1 and lop-2 will be performed. Molecular analysis of lop-l and lop-2 will be performed to learn what they encode and what roles they play in the control of cell polarity. LIN-44 antibodies will be generated to identify the cells that accumulate LIN-44. Comparison of the protein localization pattern with the localization of lin-44 transcripts will help to determine other cells that secrete LIN-44 as well as cells that receive LIN-44 signal. This information will be useful in the analysis of new genes that function with lin-44 to control cell polarity. Several Wnt genes, as well as genes that have been shown to be components of the WNT signal transduction pathway, have been implicated in several forms of cancer. The identification of novel genes that interact with lin-44 to control cell polarity may also provide insights to WNT signal transduction.